Many neurodegenerative diseases, such as Huntington's disease and Alzheimer's disease, target specific subtypes of neurons in the brain; for example, medium spiny neurons (MSNs) ofthe striatum are the neural subtype predominantly affected by Huntington's disease (HD). However, few in vitro disease models adequately mimic these neural cell subtypes or recapture in vivo human cell pathophysiology and function. Further, no therapies that stop the underlying neurodegenerative process are currently available for many such diseases, including HD. New approaches are needed to develop neural disease models from humanderived cell lines for rapid evaluation of potential therapeutics. We seek to control differentiation of human cell lines into targeted neural subtypes by engineering both the genetic make-up of patient-derived cells and by controlling the microenvironment in which the cells are differentiated. Specifically, we propose to develop methodologies for reprogramming HD patient-derived cells into neurons that mimic MSNs ofthe striatum, creating a human HD model, and to screen drug candidates within this model system. Our research plan includes identification of transcription factors that reprogram human HD patient-derived fibroblasts or IPS cells into cells with markers indicative of medium spiny neurons; determination of a microenvironment modulus that improves the yield of reprogrammed HD functional MSN-like cells; establishment of substratepresented cytokine densities that enhance yield and function of reprogrammed HD MSN-like cells to generate a functional HD model; characterization ofthe patient-derived cell culture model of HD; and screening of chemical probes in the new disease model. The patient-derived cell culture model and chemical probes identified will be invaluable resources for studying HD pathogenesis and developing a therapy to treat the disease. The approaches and resources we develop should be broadly applicable to the generation of other neural subtypes and further drug library screening towards understanding the pathogenesis of neurodegenerative diseases and halting their progression.